Brain mechanisms underlying subtle cognitive changes in the premanifest stage of Huntington disease (prHD) are not understood due to a relative dearth of functional imaging studies. Preliminary evidence suggests that alterations in regional brain activation may be sensitive to very early changes in prHD. However, as cognition depends on communication among brain regions, functional connectivity of brain networks may be a more important intermediate phenotype of early pathology. The proposed longitudinal investigation of prHD will examine functional connectivity MRI (fcMRI) measured from a resting state. Resting state fcMRI correlates with cognitive abilities and has advantages as a biomarker for longitudinal studies, yet has received scant attention in prHD. The primary goal of this projec is to use fcMRI connectivity to identify the earliest changes in brain networks in prHD and to track them longitudinally. The proposed study will employ two different, but complimentary analytic approaches to study fcMRI, as some approaches may be more sensitive to disease-relevant changes. Connectivity strength in networks will be compared between a control group and prHD individuals who are stratified into three groups based on their genetic signature of disease progression. Participants will have been studied annually for three or four consecutive years. Aim 1 will identify sensitive fcMRI markers of prHD using a region-of-interest (ROI) method. The selection of seed ROI will be informed by task-activated fMRI on tests that probe for functioning in different frontostriatal networks. The main hypothesis is that connectivity strength of seeds will be progressively weakened as prHD individuals approach diagnosis. Aim 2 will identify sensitive fcMRI markers of prHD from complex network analysis, which characterizes organizational features and information- processing capabilities of whole-brain networks. The main hypothesis is that the organization, processing efficiency, and/or functional interactions between regions will progressively weaken as prHD individuals approach diagnosis. Aim 3 will determine if fcMRI markers identified at baseline are sensitive to longitudinal decline across a three to four year period. The main hypothesis is that longitudinal changes in connectivity markers will emerge prior to changes in brain morphometry and cognitive functioning. The present proposal will also examine if fcMRI partially depends on the structural integrity of brain tissue. Each aim will include a sub-aim wherein high angular diffusion weighted imaging and structural MRI will determine if a loss in fiber-tract connectivity and volume/thinning correlate with altered connectivity in specific networks at baseline. The relative sensitivity of fcMRI and structural markers of longitudinal change will be evaluated. We will also determine if fcMRI connectivity markers selectively correlate with cognitive abilities at baseline and longitudinal changes in cognition. Altogether, the proposed multipronged approach is expected to promote a new understanding of brain networks in prHD. PUBLIC HEALTH RELEVANCE: Changes in the brain in Huntington disease (HD) begin long before a person is diagnosed, during a preclinical stage. To measure the effectiveness of potential treatments for HD, it is necessary to identify measurement tools that reliably detect changes in the brain during the preclinical stage where treatments are more likely to be successful. The primary goal of this project is to use a neuroimaging technique, namely functional connectivity MRI, to identify the earliest changes in brain connections in preclinical HD and to track these changes longitudinally.